Tranylcypromine Hemisulfate

Description

Tranylcypromine (13492-01-8) is an irreversible and non-selective monoamine oxidase inhibitor.1,2?It has been shown to inhibit the histone demethylase BHC110/LSD1.3,4

Chemical properties

A white or almost white, crystalline powder.

Originator

Parnate,SKF,UK,1960

The Uses of Tranylcypromine Hemisulfate

Monoamine oxidase inhibitor; antidepressant.

What are the applications of Application

Tranylcypromine is an irreversible inhibitor of MAO and inhibitor of histone demethylation

Manufacturing Process

A solution containing 167 grams of stabilized styrene and 183 grams of ethyl diazoacetate is cooled to 0°C and dropped into 83.5 grams of styrene with stirring, in a dry nitrogen atmosphere, at 125° to 135°C. This produced the ester ethyl 2-phenylcyclopropanecarboxylate.
A solution of the above ester (207.8 grams) and 64.5 grams of sodium hydroxide in 80 cc of water and 600 cc of ethanol is refluxed for 9 hours. The carboxylic acid of 2-phenylcyclopropane is liberated with 200 cc of concentrated hydrochloric acid. The 2-phenylcyclopropanecarboxylic acid contains 3 to 4 parts of the trans isomer to 1 part of the cis isomer. The acid is recrystallized from hot water. The pure trans isomer comes out as crystalline material (solid) while the cis isomer stays in solution. A solution of 4.62 grams of 2-phenylcyclopropanecarboxylic acid in 15 cc of dry benzene is refluxed with 4 cc of thionyl chloride for 5 hours, the volatile liquids are removed and the residue once more distilled with benzene. Fractionation of the residue yields the carbonyl chloride of 2- phenylcyclopropane.
A mixture of 15 grams of technical sodium azide and 50 cc of dry toluene is stirred and warmed and a solution of 10 grams of 2- phenylcyclopropanecarbonyl chloride in 50 cc of dry toluene is added slowly. Inorganic salts are filtered and washed well with dry benzene and the solvents are removed under reduced pressure. The RCON3 compound produced undergoes the Curtius rearrangement to RNCO + N2. The residual isocyanate is a clear red oil of characteristic odor. It is cooled to 10°C and treated cautiously with 100 cc of 35% hydrochloric acid whereupon RNCO + H2O gives RNH2 + CO2.After most of the evolution of carbon dioxide has subsided the mixture is refluxed for 13 hours, the cooled solution is diluted with 75 cc of water and extracted with three 50 cc portions of ether. The acid solution is evaporated under reduced pressure with occasional additions of toluene to reduce foaming.
The almost dry residue is cooled to 0°C and made strongly alkaline with a 50% potassium hydroxide solution. The amine is extracted into several portions of ether, dried over potassium hydroxide, the solvent removed, and the base fractioned. Reaction of the base with a half-molar quantity of sulfuric acid gives the sulfate.

Therapeutic Function

Psychostimulant

General Description

Tranylcypromine sulfate, (±)-trans-2-phenylcyclopropylaminesulfate (Parnate), was synthesized to be an amphetamineanalog (visualize the α-methyl of amphetaminecondensed onto the β-carbon atom).It does have someamphetamine-like properties, which may be why it has moreimmediate CNS-stimulant effects than agents that act byMAO inhibition alone. For MAO inhibition, there may betwo components to the action of this agent. One is thoughtto arise because tranylcypromine has structural features (thebasic nitrogen and the quasi-π character of the α- andβ-cyclopropane carbon atoms) that approximate the transitionstate in a route of metabolism of β-arylamines. As α-and β-hydrogen atoms are removed from the normal substrateof the enzyme, the quasi-π character develops over theα,β-carbon system. Duplication of the transition state permitsextremely strong, but reversible, attachment to the enzyme.Additionally, tranylcypromine is a mechanism-based inactivator.It is metabolized by MAO, with one electron of the nitrogenpair lost to flavin. This, in turn, produces homolyticfission of a carbon–carbon bond of cyclopropane, with oneelectron from the fission pairing with the remaining lone nitrogenelectron to generate an imine (protonated) and with theother residing on a methylene carbon. Thus, a free radical isformed that reacts to form a covalent bond with the enzymeor with reduced flavin to inactivate the enzyme.

References

1) Knoll?et al. (1980),?Monoamine oxidase inhibitors: Chemistry and Pharmacology; In, Sandler (ed) Enzyme inhibitors as drugs, MacMillan, London 151 2) Baker?et al. (1992),?Insights into the mechanisms of action of the MAO inhibitors phenelzine and tranylcypromine; a review, J.Psychiatry Neurosci.?17?206 3) Lee?et al. (2006),?Histone H3 lysine 4 demethylation is a target of nonselective antidepressive medications; Chemistry and Biology,?13?563 4) Schmidt and McCafferty (2007),?trans-2-Phenylcyclopropylamine is a Mechanism-Based Inactivator of the Histone Demethylase LSD1; Biochemistry,?46?4408